PLOS Science Wednesday: We’re Karim, Martin and Tim, trauma surgeons who edited and contributed research to the new PLOS Medicine Special Issue on traumatic injury – Ask Us Anything!

I am Karim Brohi, a trauma surgeon and director of the Centre for Trauma Sciences at Barts Health and Queen Mary University & London. The Centre for Trauma Sciences has a broad research into all areas of trauma care. My research especially focuses on how the body responds to critical injury and how this understanding can lead to new survivors.

And I’m Martin Schreiber, MD, the Chief of the Division of Trauma, Critical Care & Acute Care Surgery at Oregon Health & Science University. I am the head of the Trauma Research Laboratory at OHSU and we focus on resuscitation, novel blood transfusion strategies and cellular therapies in trauma.

We (Karim and Martin) recently co-edited the PLOS Medicine Special Issue on Trauma. In the collection we also published a paper on how the body's immune system responds to critical injury in the first 2 hours after injury. This is a difficult time window to study in trauma but we found it holds very specific signatures of how the body responds in the early activation of inflammation (which is the first stage of healing). We also found that some patients had a different response in certain cell death and survival pathways that were associated with them developing organ failure later in their clinical course. Organ failure is a common complication of trauma patients with a high associated death rate in its own right. It appears this immediate post-injury period is critical to understanding the response to trauma and therefore is likely to be a critical period for interventions that may improve survival and reduce complications.

And I’m Tim Billiar, Chair of the Surgery Department at the University of Pittsburgh and current President of the SHOCK Society, USA. My research focuses on how trauma, which induces a sudden and massive activation of the immune system, leads to an abnormal immune response in some individuals. This is important because this dysregulated immune response after severe injury has been linked to dysfunction of organs such as the lungs and an increased susceptibility to infections.

My colleagues and I (Tim) recently published a perspectives article titled "Time for Trauma Immunology" in PLOS Medicine as well as the results of a study in humans and mice titled "IL33 Mediated ILC2 Activation and Neutrophil IL5 production in the Lung Response After Severe Trauma: A Reverse Translation Study from and Human Cohort to a Mouse Trauma Model" in the same journal. In the perspectives piece we make the argument that trauma should be viewed like many other major disease processes that result from a dysregulated immune response (e.g. autoimmunity); as a specialized area under the broader field of immunology. We posit that this way of looking at trauma would bring the tools and expertise of the rapidly advancing field of immunology to the study of severe injury. In our experimental study, we reverse translate observations made in a large cohort of injured humans into mice genetically engineered to study the IL33-Innate Lymphocyte Cell type 2 axis. We show that an immune pathway discovered for its role in allergic airway diseases appears to contribute to acute lung injury after trauma. This study supports the idea that the study of trauma is ripe for sophisticated immunologic studies based on observations made in injured humans.

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jwis

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Jul 26, 2017, 7:41 AM

How do the immunomodulatory effects of trauma, sepsis, and blood transfusion differ from one another? do you think the inciting events and regulatory events differ from one another, or do they represent a convergence of foundational pathways?

PLOSScienceWednesday

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Jul 26, 2017, 8:58 AM

From Tim: All three can be immunosuppressive but there are major differences and the three should not be lumped together. Trauma and sepsis are too often viewed as similar insults. The trauma response is abrupt in onset resulting from tissue destruction with or without hemorrhagic shock. Sepsis is more of a syndrome and is now defined as infection with life-threatening organ dysfunction. Typically, sepsis comes on over several hours or days. If fact, unlike trauma where the onset can be easily identified by the traumatic event, the onset of sepsis is often not known. There is overlap in the responses. For example, some of the same pattern recognition receptors of the innate immune system are involved in the initial activation of the immune responses for both. I can't say that we know enough to say there is a convergence but the body uses many of the same regulatory and mediator systems during the response to trauma and severe infection. However, experimental studies have shown that modulating a pathway in a model of sepsis can have a very different consequence than that seen in a model of trauma. A lot to learn.

QuestionableSam

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Jul 26, 2017, 7:42 AM

Thank you for doing the AMA! I also have a few questions.

1) Do different patterns of trauma result in different incidences of MODS? For example, is a patient with blunt liver trauma more likely to develop this inflammatory pathway than a patient with a lacerated limb? Or, does there seem to be an exposure/response based purely on ISS?

2) Clearly this field of trauma research is still young but looking ahead, do you anticipate their being any future therapeutics to counter act this inflammatory pathway? Perhaps a new use for already established drugs similar to how TXA is now used in trauma? Steroids or short term immuno-surpression?

3) In a similar vein as Q2, in your opinion is this inflammatory pathway as significant as hypothermia, acidosis, and coagulopathy; all of which were, at one point, not understood at all in trauma. Are we going to be teaching the trauma tetrad of death in 10 years time?

4) Career advice request incoming, please ignore if not appropriate- I'm a British 4th year medical student who wishes to become a surgeon, with an interest in trauma surgery. My impression is that across most of the UK there doesn't seem to be such a thing as a "trauma surgeon" in the same way as there is in London MTCs or US Level 1 trauma centres. I'm told that this is due to change and there's a push for trauma to become a standalone surgical speciality in MTCs. For now, most trauma surgeons I've come across are most commonly general surgeons and occasionally vascular surgeons. For a student wanting to become a trauma surgeon, which speciality would you recommend pursuing? Also, do you have any other career advice?

5) Slightly cheeky to ask but I'd like to do my elective placement in trauma surgery in the USA (a level 1 centre) but many don't accept applications from overseas students. Do you know of any that do?

Many thanks

PLOSScienceWednesday

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Jul 26, 2017, 9:36 AM

Interesting question. In general, the degree and prolongation of the shock state along with the degree of tissue injury will determine whether or not a patient will develop MODS. However, there are specialized situation. For instance, the independent risk factors for ARDS are pulmonary contusion, long bone fractures and massive transfusion. The development of infections can also be associated with MODS.

One area of trauma research that is being aggressively pursued is the administration of stem cells. In general, stem cells go to the site of injury and elaborate mediators which suppress dysfunctional inflammation. These mediators are being studied and they are a promising are for future development.

Great question, the inflammatory pathway is a result of the lethal cycle. Severe injury and shock results in the acute coagulopathy of trauma which is exacerbated by fluid resuscitation. All of this produces a robust inflammatory response.
4 + 5. We plan to stick to the science.

Applying pharmacogenomics and machine learning techniques to this field will I am sure open up many new opportunities for new therapeutics or therapeutic repositioning.

QuestionableSam

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Jul 26, 2017, 10:04 AM

Thank you for the answers!

4 + 5. We plan to stick to the science.

I thought you would. Thought I'd try it anyway!

ThinkingTiger

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Jul 26, 2017, 8:05 AM

Since you study the aftermath of trauma on mice, I suppose you have to hurt/damage the mice, and many of them probably suffer endlessly? What are your ethical considerations regarding using living beings as test subjects? How many mice is it okay to kill to safe a single human life?